Our long-term objective is to understand the factors that underlie and aggravate postmenopausal bone loss, as a basis for developing effective rational strategies for managing postmenopausal osteoporosis. Impaired calcium absorption is often associated with postmenopausal osteoporosis and is believed to aggravate the bone loss in this condition. The exact cause of the impaired calcium absorption is uncertain. In the pst, 1,25(OH)2 vitamin D deficiency was considered the primary cause, but recent studies indicate that the intestine contains estrogen receptors and that estrogen may be directly involved. The hypotheses to be tested are in three parts: (1) The expression of estrogen receptors (ERs) in intestinal cells is under physiological regulation. (2) The intestinal ERs act in concert with the 1,25(OH)2 vitamin D endocrine system to regulate calcium absorption, and (3) The presence of ERs in intestinal cells has important pathophysiological implications. To evaluate these hypotheses we have four Specific Aims: (1) To examine the factors that modulate the expression and activity of intestinal estrogen receptors including athe affects of aging; (2) To assess the functional relationship between estrogen and the receptors for 1,25(OH)2 vitamin D in the intestine; (3) To examine the impact of therapy with estrogen receptor antagonist on gut absorption of calcium and on intestinal estrogen receptors in young and aged rats, and (4) To use a new mouse model with insertional disruption of the estrogen receptor gene to further investigate the role of estrogen and the estrogen receptor in intestinal calcium absorption and bone metabolism. The procedures that will be used to examine the Specific Aims include ovariectomy, immunocytochemistry, in situ hybridization, Scatchard analysis, Northern blot analysis, solution hybridization, radioimmunoassays, immunodiffusion assays, in vivo and in vitro calcium absorption and atomic absorption spectrophotometry. The studies proposed in this project are important in, at least, four respects: First, they will establish a direct physiological role for estrogen in intestinal calcium absorption. Second, they will establish the mechanism by which estrogen deficiency results in the calcium malabsorption that is believed to aggravate bone loss in postmenopausal osteoporosis and other hypoestrogenic conditions. Third, they will elucidate the functional relationship between estrogen, intestinal vitamin D receptor, and calcium absorption. Fourth, they will provide critical information on the consequences of estrogen antagonist therapy to intestinal calcium absorption.